(2S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the compound obtained from step II (0.2 g, 0.94 mmol) and K2CO3 (0.39 g, 2.8 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.16 g, 0.94 mmol) was added. After stirring the reaction mixture for 3 h at r.t., it was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[N-(2-phenylhexahydro-2,5-methanopentalen-3a(1H)-yl)glycyl]pyrrolidine-2-carbonitrile as off-white solid (0.16 g) in 48% yield. m/z (M+1) 350; 1H NMR (CDCl3) 300 MHz δ 7.35-7.16 (m, 5H), 4.4.85-4.76 (m, 1H), 3.76-3.40 (m, 2H), 3.50 (s, 2H), 2.48-2.41 (m, 1H), 2.36-2.27 (m, 2H), 2.23-2.0 (m, 6H), 1.94-1.68 (m, 4H), 1.66-1.60 (m, 1H). was added washed with water and brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.03,7]nonan-3-amine prepared as in preparation 10 (0.17 g, 0.66 mmol), and K2CO3 (0.28 g, 2.0 mmol) in DMSO (2.6 mL) at ice bath temperature was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.13 g, 0.66 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl) hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.1 g) in 40% yield. m/z (M+1) 393; 1H NMR (CDCl3) 300 MHz δ 4.80-4.75 (m, 1H), 3.70-3.37 (m, 4H), 3.36 (t, J=6.6 Hz, 2H), 3.16 (t, J=7.4 Hz, 2H), 2.43-2.37 (m, 1H), 2.35-2.13 (m, 9H), 2.05-1.99 (m, 1H), 1.95-1.75 (m, 5H), 1.70-1.63 (m, 1H), 1.54-1.47 (m, 1H). Upon completion of the reaction (by TLC) washed with water and brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.03,7]nonan-3-amine prepared as in preparation 10 (0.17 g, 0.66 mmol), and K2CO3 (0.28 g, 2.0 mmol) in DMSO (2.6 mL) at ice bath temperature was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.13 g, 0.66 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(1,1-dioxidoisothiazolidin-2-yl) hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.1 g) in 40% yield. m/z (M+1) 393; 1H NMR (CDCl3) 300 MHz δ 4.80-4.75 (m, 1H), 3.70-3.37 (m, 4H), 3.36 (t, J=6.6 Hz, 2H), 3.16 (t, J=7.4 Hz, 2H), 2.43-2.37 (m, 1H), 2.35-2.13 (m, 9H), 2.05-1.99 (m, 1H), 1.95-1.75 (m, 5H), 1.70-1.63 (m, 1H), 1.54-1.47 (m, 1H). Upon completion of the reaction (by TLC) washed with water and brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 1-(3-aminotricyclo[3.3.1.03,7]non-1-yl)pyrrolidin-2-one prepared as in preparation 9 (0.25 g, 1.1 mmol) and K2CO3 (0.46 g, 3.3 mmol) in DMSO (5 mL) at an ice bath temperature was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.2 g, 1.1 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.16 g) in 40% yield. m/z (M+1) 357; 1H NMR (CDCl3) 300 MHz δ 4.78 (d, J=7.4 Hz, 1H), 3.70-3.38 (m, 2H), 3.46 (s, 2H), 3.41 (t, J=7.0 Hz, 2H), 2.60 (dd, J=4.0, 10.2 Hz, 1H), 2.40-1.75 (m, 17H), 1.72-1.62 (m, 1H), 1.58-1.50 (m, 1H). Upon completion of the reaction (checked by TLC) washed with water and brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the hydrochloride salt obtained from step II (0.19 g, 0.98 mmol) and K2CO3 (0.53 g, 4.0 mmol) in DMSO (4.0 mL) at ice bath temperature under nitrogen atmosphere (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 1.0 mmol) was added. After stirring the reaction mixture at r.t. for 3 h, the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[N-(2-fluorohexahydro-2,5-methanopentalen-3a(1H)-yl) glycyl]pyrrolidine-2-carbonitrile as an off-white solid (0.11 g) in 38% yield. m/z (M+1) 292; 1H NMR (CDCl3) 300 MHz δ 4.80-4.73 (m, 1H), 3.77-3.32 (m, 2H), 3.52 (s, 2H), 2.50-2.42 (m, 1H), 2.87-2.08 (m, 6H), 2.0-1.60 (m, 6H), 1.50-1.42 (m, 1H). was added washed with water and brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of the amino compound obtained by step V (0.16 g, 0.95 mmol) in DMSO (4.0 mL) was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 0.96 mmol) and K2CO3 (0.4 g, 2.9 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc and washed with water ad brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{[(1-methoxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile (0.12 g) in 41% yield. m/z (M+1) 304; 1H NMR (CDCl3) 300 MHz δ 4.82-4.75 (m, 1H), 3.75-3.40-m, 4H), 3.27 (s, 3-H), 2.47-2.40 (m, 1H), 2.35-1.68 (13H), 1.57-1.41 (m, 2H). washed with water ad brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of the amino compound obtained by step V (0.16 g, 0.95 mmol) in DMSO (4.0 mL) was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.17 g, 0.96 mmol) and K2CO3 (0.4 g, 2.9 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. The reaction mixture was diluted with EtOAc and washed with water ad brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{[(1-methoxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile (0.12 g) in 41% yield. m/z (M+1) 304; 1H NMR (CDCl3) 300 MHz δ 4.82-4.75 (m, 1H), 3.75-3.40-m, 4H), 3.27 (s, 3-H), 2.47-2.40 (m, 1H), 2.35-1.68 (13H), 1.57-1.41 (m, 2H). washed with water ad brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the compound obtained in step I (280 mg, 1.5 mmol) and K2CO3 (820 mg, 6 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (205 mg, 1.2 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{[(1-hydroxytricyclo[3.3.1.03,7]non-3-yl)amino]acetyl}pyrrolidine-2-carbonitrile as a viscous liquid (150 mg) in 35% yield. m/z (M+1) 291; 1H NMR (CDCl3) 300 MHz δ 4.78 (d, J=7.0 Hz, 1H), 3.75-3.38 (m, 2H), 3.43 (s, 2H), 2.45-37 (m 1H), 2.35-1.95 (m, 8H), 1.90-1.60 (m, 6H), 1.53-1.40 (m, 2H). Upon completion of the reaction (checked by TLC) washed with water and brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of tricyclo[3.3.1.03,7]nonan-3-amine (0.28 g, 2.0 mmol) and K2CO3 (0.83 g, 6.0 mmol) in DMSO (8 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.34 g, 2.0 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[(tricyclo[3.3.1.03,7]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile as a viscous liquid (0.23 g) in 42% yield. m/z (M+1) 274; 1H NMR (CDCl3) 300 MHz δ 4.87-4.76 (m, 1H), 3.71-3.40 (m, 2H), 3.41 (s, 2H), 2.35-2.05 (m, 7H), 1.92-1.74 (m, 6H), 1.68-1.48 (m, 4H). Upon completion of the reaction (checked by TLC) washed with water and brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the compound obtained from step II (0.4 g, 1.35 mmol) and K2CO3 (0.56 g, 4.05 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.23 g, 1.35 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.21 g) in 36% yield. m/z (M+1) 434; 1H NMR (CDCl3) 300 MHz δ 7.45 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 4.86-4.76 (m, 1H), 4.67 (s (br), 1H), 3.93 (t, J=7.4 Hz, 2H), 3.75-3.40 (m, 4H), 3.48 (s, 2H), 3.46-2.38 (m, 1H), 2.36-2.23 (m, 2H), 2.23-1.70 (m, 12H), 1.65-1.57 (m, 1H). Upon completion of the reaction (checked by TLC) washed with water and brine dried over Na2SO4 the solvent was evaporated under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the compound obtained from step II (0.4 g, 1.35 mmol) and K2CO3 (0.56 g, 4.05 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.23 g, 1.35 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(2-oxoimidazolidin-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as an off-white solid (0.21 g) in 36% yield. m/z (M+1) 434; 1H NMR (CDCl3) 300 MHz δ 7.45 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 4.86-4.76 (m, 1H), 4.67 (s (br), 1H), 3.93 (t, J=7.4 Hz, 2H), 3.75-3.40 (m, 4H), 3.48 (s, 2H), 3.46-2.38 (m, 1H), 2.36-2.23 (m, 2H), 2.23-1.70 (m, 12H), 1.65-1.57 (m, 1H). Upon completion of the reaction (checked by TLC) washed with water and brine dried over Na2SO4 the solvent was evaporated under reduced pressure The crude product was purified by column chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of the compound obtained from step II (0.41 g, 1.5 mmol) and K2CO3 (0.62 g, 4.5 mmol) in DMSO (6 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.26 g, 1.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-[4-(1H-pyrrol-1-yl)phenyl]hexahydro-2,5-methanopentalen-3a (1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a white solid (0.2 g) in 32% yield as off-white solid. m/z (M+1) 415; 1H NMR (CDCl3) 300 MHz δ 7.38-7.26 (m, 4H), 7.10-7.05 (m, 2H), 6.36-6.32 (m, 2H), 4.84-4.78 (m, 1H), 3.75-3.40 (m, 2H), 3.50 (s, 2H), 2.50-2.42 (m, 1H), 2.38-2.28 (m, 2H), 2.25-2.0 (m, 6H), 2.0-1.70 (m, 7H). Upon completion of the reaction (checked by TLC) washed with water and brine dried over Na2SO4 the solvent was removed under reduced pressure The crude product was purified by column chromatography